This application's long-term goal is to elucidate the genetic regulation of the 'fibrinogen isoform as a foundation for understanding its role in cardiovascular disease. The specific hypothesis behind the proposed research is that elevated ?'fibrinogen levels lead to cardiovascular disease, based on several observations. First, purified ?'fibrinogen forms clots in vitro that are mechanically stiffer than unfractionated fibrinogen. Second, purified 'fibrinogen forms fibrin clots that are resistant to fibrinolysis. Third, decreased ?'fibrinogen levels are correlated with venous thrombosis and thrombotic microangiopathy. And fourth, elevated ?'fibrinogen levels are strongly associated with arterial cardiovascular disease, independent of total fibrinogen levels, as shown in the Stockholm Coronary Artery Disease Risk Factor study and the Framingham Heart Study. Based on these observations, this application focuses on the mechanisms underlying 'fibrinogen activity and expression. The specific aims are to: 1) Identify cis- and trans-acting SNPs that modulate 'fibrinogen expression. This will be accomplished using data from a SHARe 550K SNP set of Framingham Heart Study participants. 2) Identify candidate genes within the SNP-tagged haplotype block. This will be accomplished using the candidate gene approach to identify liver-expressed genes that are likely to regulate ?'fibrinogen levels. These specific aims will test the hypothesis that novel genome-wide SNPs, in addition to candidate SNPs within the gene (FGG), regulate the levels of ?'fibrinogen and the ratio of 'fibrinogen to total fibrinogen. Together, these specific aims will allow us to identify the most likely candidate genes from within the SNP- tagged haplotype block. Our long-term goal beyond the present R21 is to ultimately use this information to develop siRNAs to knock down expression of the candidate genes in liver cells in order to test their role in 'chain expression. PUBLIC HEALTH RELEVANCE: Fibrinogen is an isoform of the blood clotting factor fibrinogen that is a newly-emerging cardiovascular disease risk factor. This application's long-term goal is to elucidate the genetic regulation of 'fibrinogen as a foundation for understanding its role in cardiovascular disease.